Beneficial effect of a platelet-activating factor antagonist, WEB 2086, on endotoxin-induced lung injury.
We tested the hypothesis that platelet-activating factor plays an important role in promoting endotoxin-induced lung injury by studying the effect of WEB 2086, a specific platelet-activating factor receptor antagonist, on lung vascular leak in endotoxin-treated rats. Intraperitoneal injection of Salmonella enteritidis endotoxin (2 mg/kg) increased the extravascular leakage of 125I-labeled albumin in perfused lungs at 30 min, 2 h, 6 h, and 48 h. Treatment with WEB 2086 (10 mg/kg ip) either 20 min before or 30 min after endotoxin injection significantly reduced lung injury at 2 h after endotoxin (leak index: control 0.74 +/- 0.03, endotoxin 1.79 +/- 0.14, endotoxin + pretreated WEB 1.23 +/- 0.09, endotoxin + posttreated WEB 1.21 +/- 0.13). In addition, posttreatment with WEB 2086 starting at 90 min after endotoxin injection markedly reduced lung leak at 6 h (control 0.74 +/- 0.03, endotoxin 1.29 +/- 0.14, endotoxin + WEB 0.71 +/- 0.06). The protective effect of WEB 2086 was not the result of cyclooxygenase blockade because the release of thromboxane B2 by endotoxin-treated lungs was not affected by WEB 2086. Furthermore, neither pretreatment nor posttreatment with WEB 2086 significantly reduced the endotoxin-induced increase in plasma glutathione disulfide, a marker of in vivo oxidative stress. In rats given a lethal dose of endotoxin (20 mg/kg ip), posttreatment with WEB 2086, starting at 2 h after endotoxin, significantly improved survival compared with vehicle treatment. We conclude that WEB 2086 ameliorated endotoxin-induced lung injury without reducing oxidative stress in the rat and suggest that blockade of platelet-activating factor receptor may be an important therapeutic consideration in sepsis-induced acute lung vascular injury.
Chang
S W
SW
Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver 80262.
Fernyak
S
S
Voelkel
N F
NF
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000494:pharmacology* / Q000506:poisoning; D005978:Glutathione / Q000031:analogs & derivatives / Q000097:blood; D019803:Glutathione Disulfide; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010539:Permeability; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D012710:Serum Albumin, Bovine / Q000378:metabolism; D013997:Time Factors; D014227:Triazines / Q000494:pharmacology*; D014230:Triazoles
D001381:Azepines; D004731:Endotoxins; D010972:Platelet Activating Factor; D014227:Triazines; D014230:Triazoles; C052518:WEB 2086; D012710:Serum Albumin, Bovine; D005978:Glutathione; D019803:Glutathione Disulfide